Mammals respond to inflammation in part through central nervous system regulation. One set of responses is through efferent vagus nerve signaling, termed the “cholinergic anti-inflammatory pathway” (Borovikova et al., Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature: 405:458-462 (2000)). Stimulation of the efferent vagus nerve or signaling through α-bungarotoxin-sensitive nicotinic acetylcholine receptors (by, e.g., acetylcholine) attenuates systemic inflammatory responses and macrophage cytokine synthesis (Bernik, T. R. et al. Pharmacological stimulation of the cholinergic anti-inflammatory pathway. J. Exp. Med. 195:781-788 (2002); Tracey et al. Mind over immunity. FASEB J. 15:1575-1576 (2001); U.S. patent application Ser. No. 09/855,446).
Nicotinic acetylcholine receptors are a family of ligand-gated, pentameric ion channels. In humans, 16 different subunits (α1-7, α9-10, β1-4, δ, ε, and γ) have been identified that form a large number of homo- and hetero-pentameric receptors with distinct structural and pharmacological properties (Lindstrom, 1995; Leonard and Bertrand, 2001; Le Novere and Changeux, 1995). The main known function of this receptor family is to transmit signals for the neurotransmitter acetylcholine at neuromuscular junctions and in the central and peripheral nervous systems (Lindstrom, J. M. Nicotinic acetylcholine receptors. In “Hand Book Of Receptors And Channels: Ligand- And Voltage-Gated Ion Channels.” Edited by R. Alan North. CRC Press, Inc. (1995); Leonard, S. and Bertrand, D. Neuronal nicotinic receptors: from structure to function. Nicotine & Tobacco Res. 3:203-223 (2001); Le Novere, N. & Changeux, J-P. Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells. J. Mol. Evol. 40:155-172 (1995), Marubio, L. M. and Changeux, J-P. Nicotinic acetylcholine receptor knockout mice as animal models for studying receptor function. Eur. J. Pharmacol. 393:113-121 (2000); Steinlein, O. New functions for nicotine acetylcholine receptors? Behavioural Brain Res. 95:31-35 (1998)).
In a co-pending Published U.S. Patent Application No. 2004/0204355, the identity of the subunit of an acetylcholine receptor primarily responsible for attenuation of inflammatory responses was disclosed to be the α7 subunit. However, the mechanisms through which the α7 subunit acts and that would facilitate design of novel anti-inflammatory pharmaceutical agents remained unknown.
There is, however, a continued need for pharmaceutically active agents that can exploit the cholinergic anti-inflammatory pathway by activating acetylcholine receptor in a type-specific manner with minimal side effects.